scholarly journals A novel pre-clinical strategy to deliver antimicrobial doses of inhaled nitric oxide

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258368
Author(s):  
Vinicius S. Michaelsen ◽  
Rafaela V. P. Ribeiro ◽  
Edson Brambate ◽  
Aadil Ali ◽  
Aizhou Wang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lung Function ◽  
Extended Period ◽  
Inhaled Nitric Oxide ◽  
High Dose ◽  
Cytokine Analysis ◽  
Tract Infections ◽  
Standard Ventilation

Effective treatment of respiratory infections continues to be a major challenge. In high doses (≥160 ppm), inhaled Nitric Oxide (iNO) has been shown to act as a broad-spectrum antimicrobial agent, including its efficacy in vitro for coronavirus family. However, the safety of prolonged in vivo implementation of high-dose iNO therapy has not been studied. Herein we aim to explore the feasibility and safety of delivering continuous high-dose iNO over an extended period of time using an in vivo animal model. Yorkshire pigs were randomized to one of the following two groups: group 1, standard ventilation; and group 2, standard ventilation + continuous iNO 160 ppm + methylene blue (MB) as intravenous bolus, whenever required, to maintain metHb <6%. Both groups were ventilated continuously for 6 hours, then the animals were weaned from sedation, mechanical ventilation and followed for 3 days. During treatment, and on the third post-operative day, physiologic assessments were performed to monitor lung function and other significative markers were assessed for potential pulmonary or systemic injury. No significant change in lung function, or inflammatory markers were observed during the study period. Both gas exchange function, lung tissue cytokine analysis and histology were similar between treated and control animals. During treatment, levels of metHb were maintained <6% by administration of MB, and NO2 remained <5 ppm. Additionally, considering extrapulmonary effects, no significant changes were observed in biochemistry markers. Our findings showed that high-dose iNO delivered continuously over 6 hours with adjuvant MB is clinically feasible and safe. These findings support the development of investigations of continuous high-dose iNO treatment of respiratory tract infections, including SARS-CoV-2.

Inhaled nitric oxide inhibits NOS activity in lambs: potential mechanism for rebound pulmonary hypertension

1999 ◽  
Vol 277 (5) ◽  
pp. H1849-H1856 ◽  
Author(s):  
Stephen M. Black ◽  
R. Scott Heidersbach ◽  
D. Michael McMullan ◽  
Janine M. Bekker ◽  
Michael J. Johengen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Inhaled Nitric Oxide ◽  
Protein Levels ◽  
Acute Withdrawal ◽  
Inhaled No

Life-threatening increases in pulmonary vascular resistance have been noted on acute withdrawal of inhaled nitric oxide (NO), although the mechanisms remain unknown. In vitro data suggest that exogenous NO exposure inhibits endothelial NO synthase (NOS) activity. Thus the objectives of this study were to determine the effects of inhaled NO therapy and its acute withdrawal on endogenous NOS activity and gene expression in vivo in the intact lamb. Six 1-mo-old lambs were mechanically ventilated and instrumented to measure vascular pressures and left pulmonary blood flow. Inhaled NO (40 ppm) acutely decreased left pulmonary vascular resistance by 27.5 ± 4.7% ( P < 0.05). This was associated with a 207% increase in plasma cGMP concentrations ( P < 0.05). After 6 h of inhaled NO, NOS activity was reduced to 44.3 ± 5.9% of pre-NO values ( P < 0.05). After acute withdrawal of NO, pulmonary vascular resistance increased by 52.1 ± 11.6% ( P < 0.05) and cGMP concentrations decreased. Both returned to pre-NO values within 60 min. One hour after NO withdrawal, NOS activity increased by 48.4 ± 19.1% to 70% of pre-NO values ( P < 0.05). Western blot analysis revealed that endothelial NOS protein levels remained unchanged throughout the study period. These data suggest a role for decreased endogenous NOS activity in the rebound pulmonary hypertension noted after acute withdrawal of inhaled NO.

scholarly journals Inhaled Nitric Oxide Inhibits Human Platelet Aggregation, P-Selectin Expression, and Fibrinogen Binding In Vitro and In Vivo

Circulation ◽  
1998 ◽  
Vol 97 (15) ◽  
pp. 1481-1487 ◽  
Author(s):  
André Gries ◽  
Christoph Bode ◽  
Karlheinz Peter ◽  
Axel Herr ◽  
Hubert Böhrer ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Platelet Aggregation ◽  
Human Platelet ◽  
Inhaled Nitric Oxide ◽  
Human Platelet Aggregation ◽  
Fibrinogen Binding

Inhaled nitric oxide increases surfactant protein gene expression in the intact lamb

2003 ◽  
Vol 285 (3) ◽  
pp. L628-L633 ◽  
Author(s):  
Regan B. Stuart ◽  
Boaz Ovadia ◽  
Vincent V. Suzara ◽  
Patrick A. Ross ◽  
Stephan Thelitz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nitric Oxide ◽  
Dna Content ◽  
Protein Gene ◽  
Surfactant Protein ◽  
Inhaled Nitric Oxide ◽  
Mrna Content ◽  
Lung Biopsies

Inhaled nitric oxide (iNO) is used to treat a number of disease processes. Although in vitro data suggest that nitric oxide (NO) alters surfactant protein gene expression, the effects in vivo have not been studied. The objective of this study was to evaluate the effects of iNO on surfactant protein (SP)-A, -B, and -C gene expression in the intact lamb. Thirteen 4-wk-old lambs were mechanically ventilated with 21% oxygen and received iNO at 40 ppm ( n = 7) or vehicle gas ( n = 6) for 24 h. Peripheral lung biopsies were obtained at 0, 12, and 24 h and analyzed for surfactant mRNA, protein, and total DNA content. Inhaled NO increased SP-A and SP-B mRNA content by 80% from 0 to 12 h and by 78 and 71%, respectively, from 0 to 24 h. There was an increase in SP-A and SP-B protein content by 45% from 0 to 12 h, and a decrease by 70 and 65%, respectively, from 0 to 24 h. DNA content was unchanged. The mechanisms and physiological effects of these findings warrant further investigation.

scholarly journals Inhaled Nitric Oxide for postexposure chemoprophylaxis of COVID-19

2021 ◽  
Author(s):  
Antoine AbdelMassih ◽  
Rafeef Hozaien ◽  
Meryam El Shershaby ◽  
Aya Kamel ◽  
Habiba-Allah Ismail ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Systematic Review ◽  
Viral Replication ◽  
Medical Personnel ◽  
Inhaled Nitric Oxide ◽  
Cochrane Central Register ◽  
Central Register ◽  
Antiviral Role

Abstract Background: Postexposure prophylaxis has been an overlooked strategy in the context of COVID-19. Inhaled Nitric Oxide offers itself as a potential tool in this context. The aim of this systematic review was to depict previous in vivo and in vitro studies demonstrating an antiviral role for NO Methodology:Embase, Medline and the Cochrane Central Register were used to search for specific keywords such as “Nitric oxide” AND “Antiviral activity” for relevant publications up to 1st of June 2021. The systematic review was performed using PRISMA protocolResults:Twenty-one studies were identified depicting an antiviral role for Nitric Oxide. Those studies involved sixteen viruses. Only four of the depicted studies were clinical trials, while three were performed on a murine model. The remainder of the studies involved in vitro experimentation of the role of NO in halting viral replication of several viruses including SARS-CoV-2Conclusion: While early reports of NO role in the treatment of COVID-19 suggested its use for the treatment of established ARDS, NO seems to have a much earlier and more efficient prophylactic role. It inhibits a protease needed for canonical viral replication of SARS-CoV-2, namely Furin, by decreasing calcium's cytosolic levels. This might add a significant tool for postexposure chemoprophylaxis in the at-risk group, especially medical personnel.

Inhaled nitric oxide induced NOS inhibition and rebound pulmonary hypertension: a role for superoxide and peroxynitrite in the intact lamb

2006 ◽  
Vol 290 (2) ◽  
pp. L359-L366 ◽  
Author(s):  
Peter Oishi ◽  
Albert Grobe ◽  
Eileen Benavidez ◽  
Boaz Ovadia ◽  
Cynthia Harmon ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Inhaled Nitric Oxide ◽  
In Vivo Studies ◽  
Acute Increase ◽  
No Signaling ◽  
Oxide Synthase ◽  
Inhaled No

Previous in vivo studies indicate that inhaled nitric oxide (NO) decreases nitric oxide synthase (NOS) activity and that this decrease is associated with significant increases in pulmonary vascular resistance (PVR) upon the acute withdrawal of inhaled NO (rebound pulmonary hypertension). In vitro studies suggest that superoxide and peroxynitrite production during inhaled NO therapy may mediate these effects, but in vivo data are lacking. The objective of this study was to determine the role of superoxide in the decrease in NOS activity and rebound pulmonary hypertension associated with inhaled NO therapy in vivo. In control lambs, 24 h of inhaled NO (40 ppm) decreased NOS activity by 40% ( P < 0.05) and increased endothelin-1 levels by 64% ( P < 0.05). Withdrawal of NO resulted in an acute increase in PVR (60.7%, P < 0.05). Associated with these changes, superoxide and peroxynitrite levels increased more than twofold ( P < 0.05) following 24 h of inhaled NO therapy. However, in lambs treated with polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) during inhaled NO therapy, there was no change in NOS activity, no increase in superoxide or peroxynitrite levels, and no increase in PVR upon the withdrawal of inhaled NO. In addition, endothelial NOS nitration was 18-fold higher ( P < 0.05) in control lambs than in PEG-SOD-treated lambs following 24 h of inhaled NO. These data suggest that superoxide and peroxynitrite participate in the decrease in NOS activity and rebound pulmonary hypertension associated with inhaled NO therapy. Reactive oxygen species scavenging may be a useful therapeutic strategy to ameliorate alterations in endogenous NO signaling during inhaled NO therapy.

scholarly journals Coptis chinensisand Myrobalan (Terminalia chebula) Can Synergistically Inhibit Inflammatory Response In Vitro and In Vivo

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Enhui Cui ◽  
Xiaoyan Zhi ◽  
Ying Chen ◽  
Yuanyuan Gao ◽  
Yunpeng Fan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Therapeutic Potential ◽  
In Vitro Cytotoxicity ◽  
High Dose ◽  
Dependent Manner ◽  
Paw Edema ◽  
Coptis Chinensis ◽  
Anti Inflammatory

Objectives. To investigate the anti-inflammatory effect ofCoptis chinensisplus myrobalan (CM) in vitro and in vivo.Methods. The inflammation in mouse peritoneal macrophages was induced by lipopolysaccharide (LPS). Animal models were established by using ear swelling and paw edema of mouse induced by xylene and formaldehyde, respectively. In vitro, cytotoxicity, the phagocytosis of macrophages, the levels of nitric oxide (NO), induced nitric oxide synthase (iNOS), tumor necrosis factor-α(TNF-α), and interleukin-6 (IL-6) in cell supernatant were detected. In vivo, swelling rate and edema inhibitory rate of ear and paw were observed using CM-treated mice.Results. At 150–18.75 μg·mL−1, CM had no cytotoxicity and could significantly promote the growth and the phagocytosis of macrophages and inhibit the overproduction of NO, iNOS, TNF-α, and IL-6 in macrophages induced by LPS. In vivo, pretreatment with CM, the ear swelling, and paw edema of mice could be significantly inhibited in a dose-dependent manner, and the antiedema effect of CM at high dose was better than dexamethasone.Conclusion. Our results demonstrated thatCoptis chinensisand myrobalan possessed synergistically anti-inflammatory activities in vitro and in vivo, which indicated that CM had therapeutic potential for the prevention and treatment of inflammation-mediated diseases.

Significance of Platelet β-Adrenoceptors for Platelet Responses In Vivo and In Vitro

1992 ◽  
Vol 68 (06) ◽  
pp. 687-693 ◽  
Author(s):  
P T Larsson ◽  
N H Wallén ◽  
A Martinsson ◽  
N Egberg ◽  
P Hjemdahl
Keyword(s):  
Ex Vivo ◽  
High Dose ◽  
Platelet Aggregability ◽  
Adrenoceptor Agonist ◽  
Dose Infusion ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen

SummaryThe significance of platelet β-adrenoceptors for platelet responses to adrenergic stimuli in vivo and in vitro was studied in healthy volunteers. Low dose infusion of the β-adrenoceptor agonist isoprenaline decreased platelet aggregability in vivo as measured by ex vivo filtragometry. Infusion of adrenaline, a mixed α- and β-adrenoceptor agonist, increased platelet aggregability in vivo markedly, as measured by ex vivo filtragometry and plasma β-thromboglobulin levels. Adrenaline levels were 3–4 nM in venous plasma during infusion. Both adrenaline and high dose isoprenaline elevated plasma von Willebrand factor antigen levels β-Blockade by propranolol did not alter our measures of platelet aggregability at rest or during adrenaline infusions, but inhibited adrenaline-induced increases in vWf:ag. In a model using filtragometry to assess platelet aggregability in whole blood in vitro, propranolol enhanced the proaggregatory actions of 5 nM, but not of 10 nM adrenaline. The present data suggest that β-adrenoceptor stimulation can inhibit platelet function in vivo but that effects of adrenaline at high physiological concentrations are dominated by an α-adrenoceptor mediated proaggregatory action.

Preliminary Report of In vitro and In vivo Effectiveness of Dornase Alfa on SARS-CoV-2 Infection (Preprint)

2020 ◽  
Author(s):  
Hacer Kuzu Okur ◽  
Koray Yalcin ◽  
Cihan Tastan ◽  
Sevda Demir ◽  
Bulut Yurtsever ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Respiratory Tract ◽  
Mononuclear Cells ◽  
Multiple Organ ◽  
Peripheral Blood Mononuclear ◽  
Dornase Alfa ◽  
Tract Infections ◽  
Adult Peripheral Blood

UNSTRUCTURED Dornase alfa, the recombinant form of the human DNase I enzyme, breaks down neutrophil extracellular traps (NET) that include a vast amount of DNA fragments, histones, microbicidal proteins and oxidant enzymes released from necrotic neutrophils in the highly viscous mucus of cystic fibrosis patients. Dornase alfa has been used for decades in patients with cystic fibrosis to reduce the viscoelasticity of respiratory tract secretions, to decrease the severity of respiratory tract infections, and to improve lung function. Previous studies have linked abnormal NET formations to lung diseases, especially to acute respiratory distress syndrome (ARDS). Coronavirus disease 2019 (COVID-19) pandemic affected more than two million people over the world, resulting in unprecedented health, social and economic crises. The COVID-19, viral pneumonia that progresses to ARDS and even multiple organ failure, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). High blood neutrophil levels are an early indicator of SARS-CoV-2 infection and predict severe respiratory diseases. A similar mucus structure is detected in COVID-19 patients due to the accumulation of excessive NET in the lungs. Here, we show our preliminary results with dornase alfa that may have an in-vitro anti-viral effect against SARS-CoV-2 infection in a bovine kidney cell line, MDBK without drug toxicity on healthy adult peripheral blood mononuclear cells. In this preliminary study, we also showed that dornase alfa can promote clearance of NET formation in both an in-vitro and three COVID-19 cases who showed clinical improvement in radiological analysis (2-of-3 cases), oxygen saturation (SpO2), respiratory rate, disappearing of dyspnea and coughing.

Methylprednisolone on circulating eicosanoids and vasomotor tone after endotoxin

1986 ◽  
Vol 61 (1) ◽  
pp. 185-191 ◽  
Author(s):  
C. A. Hales ◽  
R. D. Brandstetter ◽  
C. F. Neely ◽  
M. B. Peterson ◽  
D. Kong ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Resistance ◽  
Systemic Blood Pressure ◽  
Physiological Effect ◽  
High Dose ◽  
Systemic Blood ◽  
Eicosanoid Production ◽  
Circulating Levels

Acute pulmonary and systemic vasomotor changes induced by endotoxin in dogs have been related, at least in part, to the production of eicosanoids such as the vasoconstrictor thromboxane and the vasodilator prostacyclin. Steroids in high doses, in vitro, inhibit activation of phospholipase A2 and prevent fatty acid release from cell membranes to enter the arachidonic acid cascade. We, therefore, administered methylprednisolone (40 mg/kg) to dogs to see if eicosanoid production and the ensuing vasomotor changes could be prevented after administration of 150 micrograms/kg of endotoxin. The stable metabolites of thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were measured by radioimmunoassay. Methylprednisolone by itself did not alter circulating eicosanoids but when given 2.5 h before endotoxin not only failed to inhibit endotoxin-induced eicosanoid production but actually resulted in higher circulating levels of 6-keto-PGF1 alpha (P less than 0.05) compared with animals receiving endotoxin alone. Indomethacin prevented the steroid-enhanced concentrations of 6-keto-PGF1 alpha after endotoxin and prevented the greater fall (P less than 0.05) in systemic blood pressure and systemic vascular resistance with steroid plus endotoxin than occurred with endotoxin alone. Administration of methylprednisolone immediately before endotoxin resulted in enhanced levels (P less than 0.05) of both TxB2 and 6-keto-PGF1 alpha but with a fall in systemic blood pressure and vascular resistance similar to the animals pretreated by 2.5 h. In contrast to the early steroid group in which all of the hypotensive effect was due to eicosanoids, in the latter group steroids had an additional nonspecific effect. Thus, in vivo, high-dose steroids did not prevent endotoxin-induced increases in eicosanoids but actually increased circulating levels of TxB2 and 6-keto-PGF1 alpha with a physiological effect favoring vasodilation.

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